scholarly journals Siderophore-Mediated Iron Acquisition Plays a Critical Role in Biofilm Formation and Survival of Staphylococcus epidermidis Within the Host

2021 ◽  
Vol 8 ◽  
Author(s):  
Fernando Oliveira ◽  
Tânia Lima ◽  
Alexandra Correia ◽  
Ana Margarida Silva ◽  
Cristina Soares ◽  
...  
Keyword(s):  
Staphylococcus Epidermidis ◽  
Iron Acquisition ◽  
Critical Role ◽  
Siderophore Production ◽  
Restricted Environment ◽  
Underlying Mechanisms ◽  
First Time ◽  
Comprehensive Study

Iron acquisition through siderophores, a class of small, potent iron-chelating organic molecules, is a widely spread strategy among pathogens to survive in the iron-restricted environment found in the host. Although these molecules have been implicated in the pathogenesis of several species, there is currently no comprehensive study addressing siderophore production in Staphylococcus epidermidis. Staphylococcus epidermidis is an innocuous skin commensal bacterium. The species, though, has emerged as a leading cause of implant-associated infections, significantly supported by an inherent ability to form biofilms. The process of adaptation from skin niche environments to the hostile conditions during invasion is yet not fully understood. Herein, we addressed the possible role of siderophore production in S. epidermidis virulence. We first identified and deleted a siderophore homolog locus, sfaABCD, and provided evidence for its involvement in iron acquisition. Our findings further suggested the involvement of siderophores in the protection against oxidative stress-induced damage and demonstrated the in vivo relevance of a siderophore-mediated iron acquisition during S. epidermidis infections. Conclusively, this study addressed, for the first time in this species, the underlying mechanisms of siderophore production, highlighting the importance of a siderophore-mediated iron acquisition under host relevant conditions and, most importantly, its contribution to survival within the host.

ADF/n-cofilin–dependent actin turnover determines platelet formation and sizing

Blood ◽  
2010 ◽  
Vol 116 (10) ◽  
pp. 1767-1775 ◽  
Author(s):  
Markus Bender ◽  
Anita Eckly ◽  
John H. Hartwig ◽  
Margitta Elvers ◽  
Irina Pleines ◽  
...  
Keyword(s):  
Actin Filament ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Actin Dynamics ◽  
Complex Process ◽  
First Time ◽  
Late Stages ◽  
Platelet Formation

Abstract The cellular and molecular mechanisms orchestrating the complex process by which bone marrow megakaryocytes form and release platelets remain poorly understood. Mature megakaryocytes generate long cytoplasmic extensions, proplatelets, which have the capacity to generate platelets. Although microtubules are the main structural component of proplatelets and microtubule sliding is known to drive proplatelet elongation, the role of actin dynamics in the process of platelet formation has remained elusive. Here, we tailored a mouse model lacking all ADF/n-cofilin–mediated actin dynamics in megakaryocytes to specifically elucidate the role of actin filament turnover in platelet formation. We demonstrate, for the first time, that in vivo actin filament turnover plays a critical role in the late stages of platelet formation from megakaryocytes and the proper sizing of platelets in the periphery. Our results provide the genetic proof that platelet production from megakaryocytes strictly requires dynamic changes in the actin cytoskeleton.

scholarly journals Bacterial competition mediated by siderophore production among the human nasal microbiota

2018 ◽  
Author(s):  
Reed M. Stubbendieck ◽  
Daniel S. May ◽  
Marc G. Chevrette ◽  
Mia I. Temkin ◽  
Evelyn Wendt-Pienkowski ◽  
...  
Keyword(s):  
Nasal Cavity ◽  
Staphylococcus Epidermidis ◽  
Iron Acquisition ◽  
Interference Competition ◽  
Human Microbiome ◽  
Human Microbiome Project ◽  
Siderophore Production ◽  
Exploitation Competition ◽  
Bacterial Competition

ABSTRACTResources available in the human nasal cavity are limited. Therefore, to successfully colonize the nasal cavity, bacteria must compete for scarce nutrients. Competition may occur directly through interference (e.g., antibiotics) or indirectly by nutrient sequestration. To investigate the nature of nasal bacterial competition, we performed co-culture inhibition assays between nasal Actinobacteria andStaphylococcusspp. We found thatStaphylococcus epidermidisisolates were sensitive to growth inhibition by Actinobacteria butStaphylococcus aureusisolates were resistant to inhibition. Among Actinobacteria, we observed thatCorynebacteriumspp. were variable in their ability to inhibitS. epidermidis.We sequenced the genomes of tenCorynebacteriumspp. isolates, including threeCorynebacterium propinquumthat strongly inhibitedS. epidermidisand seven otherCorynebacteriumspp. isolates that only weakly inhibitedS. epidermidis.Using a comparative genomics approach, we found that theC. propinquumgenomes were enriched in genes for iron acquisition and encoded a biosynthetic gene cluster (BGC) for siderophore production, absent in the non-inhibitoryCorynebacteriumspp. genomes. Using a chromeazurol S assay, we confirmed thatC. propinquumproduced siderophores. We demonstrated that iron supplementation rescuedS. epidermidisfrom inhibition byC. propinquum, suggesting that inhibition was due to iron restriction through siderophore production. Using comparative metabolomics, we identified the siderophore produced byC. propinquumas dehydroxynocardamine. Finally, we confirmed that the dehydroxynocardamine BGC is expressedin vivoby analyzing human nasal metatranscriptomes from the NIH Human Microbiome Project.Together, our results suggest that bacteria produce siderophores to compete for limited available iron in the nasal cavity and improve their fitness.IMPORTANCEWithin the nasal cavity, interference competition through antimicrobial production is prevalent. For instance, nasalStaphylococcusspp. strains can inhibit the growth of other bacteria through the production of nonribosomal peptides and ribosomally synthesized and post-translationally modified peptides. In contrast, bacteria engaging in exploitation competition modify the external environment to prevent competitors from growing, usually by depleting access to essential nutrients. As the nasal cavity is a nutrient limited environment, we hypothesized that exploitation competition occurs in this system. We determined thatCorynebacterium propinquumproduces an iron-chelating siderophore and is able to use this molecule to sequester iron and inhibit the growth ofStaphylococcus epidermidis.Further, we found that the genes required for siderophore production are expressedin vivo.Thus, though siderophore production by bacteria is often considered a virulence trait, our work indicates that bacteria may produce siderophores to compete for limited iron in the human nasal cavity.

scholarly journals T cells expressing specific V beta elements regulate immunoglobulin E production and airways responsiveness in vivo.

1993 ◽  
Vol 177 (4) ◽  
pp. 1175-1180 ◽  
Author(s):  
H Renz ◽  
K Bradley ◽  
J Saloga ◽  
J Loader ◽  
G L Larsen ◽  
...  
Keyword(s):  
T Cells ◽  
Immunoglobulin E ◽  
Critical Role ◽  
Specific Ige ◽  
Specific Immunoglobulin ◽  
Cutaneous Hypersensitivity ◽  
First Time ◽  
Draining Lymph Nodes

The role of T cells expressing specific V beta elements was examined in the regulation of allergen-specific immunoglobulin (Ig)E production and airways responsiveness (AR). In BALB/c mice, inhalation of the allergen ovalbumin (OVA) induced an IgE anti-OVA response, immediate cutaneous reactivity, and increased AR. These results were associated with an expansion of V beta 8.1/8.2 T cells in local draining lymph nodes of the airways and the lung. Transfer of V beta 8.1/8.2 T cells from sensitized mice stimulated an IgE anti-OVA response, immediate cutaneous hypersensitivity, and increased AR in naive syngeneic recipients. In contrast, OVA-reactive V beta 2 T cells inhibited these effects. These data demonstrate for the first time that T cells with different V beta specificities play a critical role in the in vivo regulation of allergen-specific IgE production and AR.

scholarly journals Critical Role of the Interleukin-17/Interleukin-17 Receptor Axis in Regulating Host Susceptibility to Respiratory Infection with Chlamydia Species

2009 ◽  
Vol 77 (11) ◽  
pp. 5059-5070 ◽  
Author(s):  
Xiaohui Zhou ◽  
Qiangwei Chen ◽  
Jessica Moore ◽  
Jay K. Kolls ◽  
Scott Halperin ◽  
...  
Keyword(s):  
Respiratory Infection ◽  
Critical Role ◽  
Lung Parenchyma ◽  
Host Susceptibility ◽  
Interleukin 17 ◽  
Chlamydia Muridarum ◽  
Inflammatory Protein ◽  
First Time

ABSTRACT The specific contribution of interleukin-17/interleukin-17 receptor (IL-17/IL-17R)-mediated responses in regulating host susceptibility against obligatory intracellular Chlamydia infection was investigated in C57BL/6 and C3H/HeN mice during Chlamydia muridarum respiratory infection. We demonstrated that Chlamydia stimulated IL-17/IL-17R-associated responses in both Chlamydia-resistant C57BL/6 and Chlamydia-susceptible C3H/HeN mice. However, C3H/HeN mice developed a significantly greater IL-17/IL-17R-associated response than C57BL/6 mice did. This was reflected by an increase in IL-17 mRNA expression, a higher recall IL-17 production from splenocytes upon antigen restimulation, and higher production of Th17-related cytokines (IL-23 and IL-6) and chemokines (chemokine [C-X-C motif] ligand 2 [CXCL1]/keratinocyte-derived chemokine [KC] and CXCL2/macrophage inflammatory protein 1 [MIP2]) in C3H/HeN mice than in C57BL/6 mice. Furthermore, C3H/HeN mice displayed a massive accumulation of activated and preactivated neutrophils in the airway and lung parenchyma compared to their C57BL/6 counterparts. We further demonstrated that the skewed IL-17/Th17 profile in C3H/HeN mice was predisposed by a higher basal level of IL-17 receptor C (IL-17RC) expression and then further amplified by a higher inducible IL-17RA expression in lungs. Most importantly, in vivo delivery of IL-17RA antagonist that resulted in a 50% reduction in the neutrophilic infiltration in lungs was able to reverse the susceptible phenotype of C3H/HeN mice to respiratory Chlamydia infection. Thus, our data for the first time have demonstrated a critical role for the IL-17/IL-17R axis in regulating host susceptibility to Chlamydia infection in mice.

Autophagy Modulators and Neuroinflammation

2020 ◽  
Vol 27 (6) ◽  
pp. 955-982 ◽  
Author(s):  
Kyoung Sang Cho ◽  
Jang Ho Lee ◽  
Jeiwon Cho ◽  
Guang-Ho Cha ◽  
Gyun Jee Song
Keyword(s):  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Scientific Interest ◽  
Therapeutic Tools ◽  
Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Role of Vascular Endothelial Growth Factor (VEGF) in Human Embryo Implantation: Clinical Implications

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 253
Author(s):  
Xi Guo ◽  
Hong Yi ◽  
Tin Chiu Li ◽  
Yu Wang ◽  
Huilin Wang ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Recurrent Miscarriage ◽  
Embryo Implantation ◽  
Critical Role ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Underlying Mechanisms ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor that plays a critical role in various physiological and pathological processes. VEGF also contributes to the process of embryo implantation by enhancing embryo development, improving endometrial receptivity, and facilitating the interactions between the developing embryo and the endometrium. There is a correlation between the alteration of VEGF expression and reproductive failure, including recurrent implantation failure (RIF) and recurrent miscarriage (RM). In order to clarify the role of VEGF in embryo implantation, we reviewed recent literature concerning the expression and function of VEGF in the reproductive system around the time of embryo implantation and we provide a summary of the findings reported so far. We also explored the effects and the possible underlying mechanisms of action of VEGF in embryo implantation.

scholarly journals Role of interleukins in the pathogenesis of pulmonary fibrosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Xin She ◽  
Qing Yang Yu ◽  
Xiao Xiao Tang
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Strategy ◽  
Future Directions ◽  
Regulation Mechanisms ◽  
Underlying Mechanisms ◽  
Multiple Cells ◽  
The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

scholarly journals The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Brianna J. Klein ◽  
Anagha Deshpande ◽  
Khan L. Cox ◽  
Fan Xuan ◽  
Mohamad Zandian ◽  
...  
Keyword(s):  
Critical Role ◽  
Cellular Transformation ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Nucleosome Core ◽  
Stem And Progenitor Cells ◽  
Transforming Activity

AbstractChromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

scholarly journals Secreted KIAA1199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1-dependent manner

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Zhang ◽  
Guoyu Yin ◽  
Heping Zhao ◽  
Hanzhi Ling ◽  
Zhen Xie ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hyaluronic Acid ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Intracellular Degradation ◽  
Main Pathway ◽  
First Time

AbstractIn inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.

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